Blogging from the One Mind for Research Summit

One Mind for Research Sessions for All

In May I attended an ambitious, inspiring conference in Boston called "Next Frontier of the Brain: Imagining the Next Decade of Neuroscience Research & Development." Over three days, we heard more than 20 hours of lectures, advocacy, and discussion about how the science—and the technology supporting it—have reached a point of great promise. Now what's needed is a massive push to find good therapies for people. See for yourself: Videos of the sessions and one-on-one interviews with some of the researchers are now posted on the Science Network's site.

At the forum, held in Boston May 23–25, former Congressman Patrick Kennedy and longtime advocate Garen Staglin brought together more than 300 people doing brain research, developing biotech and drug treatments, treating patients, advocating for patients and families, and working the political aisles. "If we take away one idea from this event, I hope it's the idea of the things we need to do to better take care of the people we love," Kennedy said. "The time is now." (See Kennedy's call to action (26 min))

The conference was the first public event by the One Mind for Research campaign, whose goal is "to significantly reduce the U.S. burden of disability due to brain disorders." Steven Hyman, outgoing provost of Harvard and a Dana Alliance member, coordinated the science presenters; they and other researchers created a blueprint of research goals, released at the event: "A Ten-Year Plan for Neuroscience: From Molecules to Brain Health" (PDF). The first part of the document describes where we stand, why now is the right time to push, and what we should aim for in general. The second part has specific (and often technical) goals in six areas:

Molecules, cells, and synapses

Neural circuits

Development, plasticity, and repair

Behavioral, cognitive, and systems neuroscience

Neurobiology of disease

Clinical neuroscience

The second part is a "work-in-progress," intended to change as scientists and funders discuss the ideas, and lead to specific scientific proposals. As Dr. Hyman says in the introduction, "It is time for investment and a concerted effort. The cost of inaction would prove staggering." Here's Dr. Hyman's introduction on the first day (38 min):

I'll have a lot more to say about the conference over the next few weeks, but first I want to watch the videos. The conference flew by, but the 20 hours of science were packed with valuable information and I don’t want to overlook anything.

--Nicky Penttila

¯ ¯ ¯

Targeting the Effects of War on the Brain

War carries many consequences, including the "invisible wounds" sustained by the brain: post-traumatic stress disorder, chronic pain, and concussions. At one session at the recent "Next Frontier of the Brain" forum in Boston, researchers described progress in treating these wounds, and what we need to do to learn how to heal all injured veterans, as well as their civilian brothers and sisters. The session was recorded by the Science Network (video and mp3 audio available) and you'll find it below; the science presentations start at the 20-minute mark.

Elizabeth Phelps of New York University began by describing the neurobiology of PTSD. "In normal fear, there's this delicate balance between these brain systems that assures that fear is expressed when there's a real threat, but when the threat has passed, and now you know the situation is safe, or when the context is safe, the fear is not expressed." What happens in PTSD, scientists think, is that this balance is disrupted. "So the amygdala [part of the fear circuit] now has a stronger influence on the expression of behavior, and it is not as easily inhibited."

This affects cognitive processing as well as emotional processing. For example, Phelps said, "Even though these patients tend to show very robust memories of the traumatic events that they don't seem to be able to forget, after they acquire PTSD they show relatively poor memory function in everyday life."

Current treatments work for some people, but psychotherapies rely on cognitive abilities that may be offline in those with PTSD, and while drugs resolve symptoms they may not fix the underlying problem. In addition to investigating new drugs, researchers are trying another approach: understanding resilience.

Up to one-third of combat veterans will show symptoms of PTSD, Phelps said. "But this means at a minimum about 70 percent of people who experience trauma do not develop PTSD, and the question is: Can we identify who they are?" There are signs that a number of factors may be linked to resilience, including prior life experience, social support, genetic variation, and neural vulnerabilities caused by traumatic brain injury or perhaps just due to individual variation. "All of these can work in combination with the nature of the trauma to promote resilience—or not," she said.

"If we understand what makes somebody resilient we could do one of two things: We could either not let those people who are vulnerable be exposed to combat situations, or, perhaps, we can develop new treatments that we can now make those vulnerable populations less vulnerable." [In the video, her presentation runs from the 20-minute mark to 37:00.]

Clifford J. Woolf, director of the program in neurobiology at Children's Hospital Boston, pointed out that when people count the costs of disease, they often miss the biggest one: "The commonest cause of complaint, why patients go to see their physicians, happens to be pain."

And while we have made enormous progress in promoting survival and great advances in rehabilitation, "in fact an area that has really lagged behind relates to the pain associated with combat injury," he said.

Pain is not a symptom but a disease state, a physical injury to the nervous system, Woolf said. "While plasticity is a critical component of how the brain enables us to learn and to retain information, the same modifiability of the nervous system can also contribute to disease states," he said.

A promising current approach to understanding pain is the same approach as that for PTSD – understanding individual differences. People with apparently identical injuries do not develop identical levels of pain—or any pain, sometimes, he said. Researchers are looking for genetic variations and also investigating the differences in people who have Mitchell's disease (a hypersensitivity to pain) and people who cannot feel any pain at all. "If we know who has a high risk of developing pain, the treatment may be quite different from those individuals who have a low risk," Woolf said. [In the video, his presentation runs from 37:30 to 55:03.]

Col. Geoffrey Ling of the Defense Advanced Research Projects Agency (DARPA) described how he and other military medical workers have reshaped their approach to traumatic brain injuries (TBI). He started by showing graphically what people in war zones experience, describing three of his patients and how timely treatment can lead to recovery from even serious wounding. [In the video, his presentation runs from 55:30 to 1:16:00.]

Then he showed a series of frightening video examples of explosions in a lab setting and in the towns and mountains of Iraq and Afghanistan, illustrating the violence of the blast itself and also the force of the shockwaves that flow out of it. The latter blasts injured and killed several people, and similar blasts continue to occur. "That's what the urgency of what we are doing is," Ling said.

Ling and his colleagues have created the first system-wide approach to concussion, including a diagnostic tool, clinical guidelines, return-to-duty guidelines, and mandatory TBI screening of all people near a blast.

Why mandatory screening? "Because these are not patients that come to you; these are patients we must go to," Ling said. "We had to change the paradigm of expecting somebody to report in and say 'I am hurt' when we realized that they may not know they are hurt—particularly the PTSD patients."

These guidelines are just a start, Ling said. "And we want to build on it," by publishing their results and experiences and learning from civilian experiences such as NFL players' records. "Where it goes now is research, research, research."

Elizabeth Phelps agreed. "It is my hope that, with the continued efforts of basic and applied research in brain science over the next decades, in the future when we see soldiers like this we can be fairly confident that none of them will suffer the debilitating effects of PTSD. And that all of our soldiers who survive the physical risks of war have the happy homecoming and bright future they so deserve."

No Expiration Date on PTSD

Even though I live near Washington, DC, I'm not a politics maven. I remember when Sen. Max Cleland lost his seat in 2002, but I hadn't heard anything about him since, so I figured he had happily retired from the often-dirty fray. I could not have been more wrong.

I saw him again last month when he spoke to the researchers, biotech workers, and advocates at the "Next Frontier of the Brain" forum in Boston. Instead of relaxing after his decades of public service, Cleland had spiraled down into the abyss of PTSD—more than 40 years after he was grievously wounded in Vietnam.

"People who overcome, especially, physical injuries…usually do it by means of having some kind of purpose in their life. I had a strong meaning and purpose; it was called politics, government service."

"But then I lost [the election]. I lost my sense of meaning and purpose and destiny, vision. And at that point, then the reality of the wounding came into play. Then I realized, only recently, I was dealing with something that was much bigger than I was. And that was the basic, fundamental aspect of your brain.

"I went down into a massive, deep, dark depression sparked by massive anxiety and what we now know flooding of adrenaline and cortisol into the system—and all of that stuff came flooding back from forty-some-odd years ago, just like I was on the battlefield again, dying, overwhelmed, overcome." At one point, he said, he was so disabled, emotionally and cognitively, that he lost the ability to read.

Cleland went back to Walter Reed hospital, where he had first recovered from the loss of parts of three limbs in 1968. This time, the doctors helped him start to heal his inner wounds. "Thank God, patient help, trauma counseling at Walter Reed…anti-depressant for a while, I began to recover. And I'm beginning to restore my sense of self and all these other things, and then, you know, magically the emotions come back, and the cerebral capability comes back, and then you begin to start thinking again about meaning and purpose."

Cleland also tells his story in the documentary film Halfway Home, which follows several veterans through their first years home from war. The film had its Boston premiere as part of the forum; its director, Paul Freedman, and narrator, Martin Sheen, joined Cleland to talk about the film after the showing.

In the film, Cleland describes one of his low moments at Walter Reed, sitting and sobbing uncontrollably and then hearing, through the wall, his own voice, cheerful. It was from a video he had recorded long ago to inspire newly wounded patients to not give up.

"I had no idea for years, for decades, that I might have some kind of something called post-traumatic stress disorder," he said at the forum. "For those who have been wounded, whether they have been physically wounded or not, when they have been traumatized, that old horse, that thousand-pound steed in your mind, has been spooked. It has been spooked. And if it has been spooked numerous times, it ain't ever forgetting."

"And so anything that comes along and spooks that horse—we call it triggers, nowadays—then you're off and running. You're liable to be thrown off the horse and dragged along the ground."

Now Cleland is secretary of the American Battle Monuments Commission and, as always, a strong advocate for veterans. And he wrote a book about his journey, Heart of a Patriot: How I Found the Courage to Survive Vietnam, Walter Reed and Karl Rove. He ended his remarks with a plea to the audience: "Those of us that have made that journey and hundreds of thousands, really, millions of young Americans who have put their lives on the line for the rest of us, need you. We need you."

Just before I left to travel to the conference, I read in my local paper of a hit-and-run driver who had killed a pedestrian in the dark of night. The top of the story described the accident and suggested alcohol was involved. In the middle of the story, I read that the driver, who was found disoriented in a nearby field, was a friend of the person he had allegedly hit; they were both headed home in the same neighborhood. At the end of the story, I learned that the driver was recently returned from a war zone. Now when I hear these stories, I wonder: Was he showing symptoms of PTSD? Was he getting the re-entry care he needed? Are there others like him we must help?

--Nicky Penttila

¯ ¯ ¯

The Blasted Brain

Traumatic brain injury (TBI), the signature injury of the current U.S. wars, calls for the nation's best "emergency medicine," Kevin Kit Parker told a group of top scientists, medicine makers, and policy makers, this spring at the One Mind for Research conference in Boston.

"Certainly TBI, as it affects the force, is a national security issue, and it's certainly an emergency issue." Like the race to the moon and the Manhattan project, he said, TBI is an emergency science project with national security at stake and a need to move rapidly.

"You've got young NCOs [non-commissioned officers], young soldiers out there that have been blown up a dozen times, a dozen times they've suffered a traumatic brain injury, since 9/11. We have this growing cadre of our professional warriors that are out there, that are walking around, and the concern is, what does the future hold for them?"

The timelines of TBI damage range from nanoseconds to years. "The data now is pretty clear that TBI can potentiate a variety of neurodegenerative diseases, including Parkinson's and Alzheimer's disease," Parker said. "So the outlook for these young soldiers is kind of bleak right now."

Parker, a professor at Harvard, has also served multiple tours in Afghanistan in the Army Reserve, tending the wounded immediately after impact and observing their recovery on base and back in the United States. The experiences led him to expand his research focus from the physics of the heart to the brain. "When people started trying to kill me with IED's I thought I'd better get a piece of this," he said.

His background also led to an unusual approach to the problem, or at least unusual for neuroscientists. "I'm an infantry officer in the reserve, and I'm not a physician, I'm a physicist, so I look at things in terms of scaling laws." Interested in how mechanical energy (such as from blasts) affects neurons, he and the people in his lab decided to try to build physical models of blast injury from molecule to cell and from cell to tissue.

"We use tissue engineering as a tool, including blasting neurons," he said. "What we found right away is that we can mimic some of the things that the neuropathologists are reporting that they're seeing in patients."

"Now that we've got all these models, we're working on developing a systematic understanding of the mechanical forces required to injure these neurons, these vascular tissues, and understand the chemical cascades that are turned on by these mechanical forces." If they understand these chemical cascades, they could start to identify which molecules along the cascade are the most vulnerable—and which might be easily reached by drugs and other therapies.

Part of emergency medicine is exploring many avenues simultaneously, Parker said. His theory is it's diffused axonal injury that leads to damage from TBI, but researchers need to work on multiple hypotheses, to "flank the problem" with the outside-the-box ideas until someone finds some badly needed solutions.

One giant challenge: "We need to build a brain," he said. "Everyone would benefit from having a brain in their [laboratory] dish to work on:" a 1 mm3 piece of brain that mimics the neural microenvironment, scalable so what people discover in the lab can be tested in drug-maker's wide-assay studies. He's working on it.

In addition, "we need to push the science as far forward [on the battlefield] as we possibly can," he said. "It might be a diffusion tensor imager that we put downrange, it might be a biomarkers lab that we put downrange … so we can understand, as these soldiers come off the battlefield, what's happening to them, rather than waiting 6 months, 12 months before they present at a VA emergency room."

"The whole idea is that when these guys [medics] run up there to pull these broken kids out of this MRAP [armored vehicle], that there's a whole team behind them supporting them," he said. "If I run up there and this kid's got a leg dangling off, I know how to apply a tourniquet to him. If I run up there and he's got his bell rung, I got no way of treating this guy right now. And right now he's at the genesis of these neurodegenerative diseases that might not appear for 20-30 years down the road."

The Science Network also did a wide-ranging interview with Parker, on work in the lab, his experience in Afghanistan, how he got started in science, and his passionate advocacy for his compatriots in the field. (22 min). It's also well worth a listen.